Molecular complexity of diffuse large B-cell lymphoma: Can it be a roadmap for precision medicine?

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma; it features extreme molecular heterogeneity regardless of the classical cell-of-origin (COO) classification. Despite this, the standard therapeutic approach is still immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone—R-CHOP), which allows a 60% overall survival (OS) rate, but up to 40% of patients experience relapse or refractory (R/R) disease. With the purpose of searching for new clinical parameters and biomarkers helping to make a better DLBCL patient characterization and stratification, in the last years a series of large discovery genomic and transcriptomic studies has been conducted, generating a wealth of information that needs to be put in order. We reviewed these researches, trying ultimately to understand if there are bases offering a roadmap toward personalized and precision medicine also for DLBCL

Absolute quantification of the pretreatment PML-RARA transcript defines the relapse risk in acute promyelocytic leukemia.

In this study we performed absolute quantification of the PML-RARA transcript by droplet digital polymerase chain reaction (ddPCR) in 76 newly diagnosed acute promyelocytic leukemia (APL) cases to verify the prognostic impact of the PML-RARA initial molecular burden. ddPCR analysis revealed that the amount of PML-RARA transcript at diagnosis in the group of patients who relapsed was higher than in that with continuous complete remission (CCR) (272 vs 89.2 PML-RARA copies/ng, p = 0.0004, respectively). Receiver operating characteristic analysis detected the optimal PML-RARA concentration threshold as 209.6 PML-RARA/ng (AUC 0.78; p < 0.0001) for discriminating between outcomes (CCR versus relapse). Among the 67 APL cases who achieved complete remission after the induction treatment, those with > 209.6 PML-RARA/ng had a worse relapse-free survival (p = 0.0006). At 5-year follow-up, patients with > 209.6 PML-RARA/ng had a cumulative incidence of relapse of 50.3% whereas 7.5% of the patients with suffered a relapse (p < 0.0001). Multivariate analysis identified the amount of PML-RARA before induction treatment as the sole independent prognostic factor for APL relapse. Our results show that the pretreatment PML-RARA molecular burden could therefore be used to improve risk stratification in order to develop more individualized treatment regimens for high-risk APL cases

ADAMTS2 gene dysregulation in T/myeloid mixed phenotype acute leukemia.

Background: Mixed phenotype acute leukemias (MPAL) include acute leukemias with blasts that express antigens of more than one lineage, with no clear evidence of myeloid or lymphoid lineage differentiation. T/myeloid (T/My) MPAL not otherwise specified (NOS) is a rare leukemia that expresses both T and myeloid antigens, accounting for less than 1% of all leukemias but 89% of T/My MPAL. From a molecular point of view, very limited data are available on T/My MPAL NOS. Case presentation: In this report we describe a T/My MPAL NOS case with a complex rearrangement involving chromosomes 5 and 14, resulting in overexpression of the ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2) gene due to its juxtaposition to the T cell receptor delta (TRD) gene segment. Conclusion: Detailed molecular cytogenetic characterization of the complex rearrangement in the reported T/My MPAL case allowed us to observe ADAMTS2 gene overexpression, identifying a molecular marker that may be useful for monitoring minimal residual disease. To our knowledge, this is the first evidence of gene dysregulation due to a chromosomal rearrangement in T/My MPAL NOS. Keywords: Mixed phenotype acute leukemia, ADAMTS2, TRD, Complex chromosomal rearrangement, Promoter swapping, Gene dysregulatio

IRF4 expression is low in Philadelphia negative myeloproliferative neoplasms and is associated with a worse prognosis

Interferon regulatory factor 4 (IRF4) is involved in the pathogenesis of various hematologic malignancies. Its expression has been related to the negative regulation of myeloid-derived suppressor cells (MDSCs) and the polarization of anti-inflammatory M2 macrophages, thereby altering immunosurveillance and inflammatory mechanisms. An abnormal inflammatory status in the bone marrow microenvironment of myeloproliferative neoplasms (MPNs) has recently been demonstrated; moreover, in chronic myeloid leukemia a downregulated expression of IRF4 has been found. In this context, we evaluated the IRF4 expression in 119 newly diagnosed consecutive Philadelphia negative MPNs (Ph- MPNs), showing a low expression among the MPNs phenotypes with a more significant decrease in primary myelofibrosis patients. Lower IRF4 levels were associated with JAK2 + and triple negatives cases carrying the worst prognosis. Furthermore, the IRF4 levels were related to leukemic transformation and a shorter leukemia-free survival; moreover, the risk of myelofibrosis transformation in polycythemia vera and essential thrombocythemia patients was more frequent in cases with lower IRF4 levels. Overall, our study demonstrates an IRF4 dysregulated expression in MPNs patients and its association with a worse prognosis. Further studies could validate these data, to improve our knowledge of the MPNs pathogenesis and confirm the IRF4 role as a new prognostic factor

Nanopore sequencing approach for immunoglobulin gene analysis in chronic lymphocytic leukemia

The evaluation of the somatic hypermutation of the clonotypic immunoglobulin heavy variable gene has become essential in the therapeutic management in chronic lymphocytic leukemia patients. European Research Initiative on Chronic Lymphocytic Leukemia promotes good practices and standardized approaches to this assay but often they are labor-intensive, technically complex, with limited in scalability. The use of next-generation sequencing in this analysis has been widely tested, showing comparable accuracy and distinct advantages. However, the adoption of the next generation sequencing requires a high sample number (run batching) to be economically convenient, which could lead to a longer turnaround time. Here we present data from nanopore sequencing for the somatic hypermutation evaluation compared to the standard method. Our results show that nanopore sequencing is suitable for immunoglobulin heavy variable gene mutational analysis in terms of sensitivity, accuracy, simplicity of analysis and is less time-consuming. Moreover, our work showed that the development of an appropriate data analysis pipeline could lower the nanopore sequencing error rate attitude

RUNX1 gene alterations characterized by allelic preference in adult acute myeloid leukemia

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Neglected Tropical Diseases in Sub-Saharan Africa: Review of Their Prevalence, Distribution, and Disease Burden

The neglected tropical diseases (NTDs) are the most common conditions affecting the poorest 500 million people living in sub-Saharan Africa (SSA), and together produce a burden of disease that may be equivalent to up to one-half of SSA's malaria disease burden and more than double that caused by tuberculosis. Approximately 85% of the NTD disease burden results from helminth infections. Hookworm infection occurs in almost half of SSA's poorest people, including 40–50 million school-aged children and 7 million pregnant women in whom it is a leading cause of anemia. Schistosomiasis is the second most prevalent NTD after hookworm (192 million cases), accounting for 93% of the world's number of cases and possibly associated with increased horizontal transmission of HIV/AIDS. Lymphatic filariasis (46–51 million cases) and onchocerciasis (37 million cases) are also widespread in SSA, each disease representing a significant cause of disability and reduction in the region's agricultural productivity. There is a dearth of information on Africa's non-helminth NTDs. The protozoan infections, human African trypanosomiasis and visceral leishmaniasis, affect almost 100,000 people, primarily in areas of conflict in SSA where they cause high mortality, and where trachoma is the most prevalent bacterial NTD (30 million cases). However, there are little or no data on some very important protozoan infections, e.g., amebiasis and toxoplasmosis; bacterial infections, e.g., typhoid fever and non-typhoidal salmonellosis, the tick-borne bacterial zoonoses, and non-tuberculosis mycobaterial infections; and arboviral infections. Thus, the overall burden of Africa's NTDs may be severely underestimated. A full assessment is an important step for disease control priorities, particularly in Nigeria and the Democratic Republic of Congo, where the greatest number of NTDs may occur

Beam test performance of a prototype module with Short Strip ASICs for the CMS HL-LHC tracker upgrade

The Short Strip ASIC (SSA) is one of the four front-end chips designed for the upgrade of the CMS Outer Tracker for the High Luminosity LHC. Together with the Macro-Pixel ASIC (MPA) it will instrument modules containing a strip and a macro-pixel sensor stacked on top of each other. The SSA provides both full readout of the strip hit information when triggered, and, together with the MPA, correlated clusters called stubs from the two sensors for use by the CMS Level-1 (L1) trigger system. Results from the first prototype module consisting of a sensor and two SSA chips are presented. The prototype module has been characterized at the Fermilab Test Beam Facility using a 120 GeV proton beam

Lymphatic filariasis elimination: progress in global programme development

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) is an innovative, public-private partnership for health improvement. The progress made since the programme was initiated, in 1998, is here reviewed. The programme is largely based on the regular mass administration of albendazole with either ivermectin (Mectizan(R)) or diethylcarbamazine. Both albendazole and ivermectin have been donated by their manufacturers, for as long as necessary. The first national campaigns based on these drugs commenced in late 1999. Since then, rapid progress has been made in confirming the safety of the drug combinations, establishing a regional approach, and recognizing that experiences, epidemiological settings, health systems, the best drug combinations and disease burdens all vary with the country involved. There is a continuing trend towards decentralization, and this should lead to greater regional and national ownership and more inter-country activities. The progress made in mapping the geographical distribution of lymphatic filariasis (LF), by designated implementation units and, ultimately, by country, is also summarized. Country-specific methods of social mobilization and drug distribution, that are compatible with health planning at central and district level, need to be developed. However, the assessment of coverage by mass drug administration (MDA) needs to be strengthened, to allow reliable national monitoring and inter-country or inter-region comparisons. Valuable contributions made by non-governmental development organizations (NGDO) and civil society organizations (CSO) are acknowledged, such organizations (and particularly local NGDO) should be encouraged to help more in implementing the various activities at district level. The GPELF has developed during an era of considerable change in international health policy. The programme can contribute to the relief of poverty, as LF is closely associated with low-income communities in the least developed countries and MDA is a pro-poor intervention. There are clear opportunities for linking the activities of the GPELF (which uses cheap or free drugs that bring considerable incidental health benefits, in addition to arresting the transmission of the parasites causing LF) with other health interventions. New evidence indicates that annual treatments with antifilarial drugs greatly reduce the clinical abnormalities of the disease. The programme has expanded rapidly, with the annual number of people treated rising from 2.9 million (in 12 countries) in the year 2000 to 25.89 million (in 22 countries) in 2001 and an estimated 80 million (in 34 countries) in 2002. At the recent meeting of the Global Alliance, held in New Delhi in May 2002, a significant but realistic challenge - of scaling-up the programme to cover up to 350 million of those at risk, by the end of 2005 - was set. The rate of growth necessary to meet this target presents considerable strategic and managerial challenges to all of the partners involved in the programme, from the development of synergies with other, large-scale, public-health interventions to the logistics of drug manufacture, shipping and local transportation and resolving the problems of social mobilization, reporting, evaluation and monitoring on such a scale. Such challenges are, however, easily outweighed by the potential benefits of success. If the international health community cannot provide the necessary support to complement the investments being made by the endemic countries (as they scale-up their LF-elimination campaigns and ensure yearly access to two free and efficacious drugs that bring major benefits to those treated), significant progress in the control of other infectious diseases becomes a very distant goal